Compounds and compositions for delivering active agents

ABSTRACT

Carrier compounds and compositions therewith which are useful in the delivery of active agents are provided. Methods of administration and preparation are provided as well.

FIELD OF THE INVENTION

The present invention relates to compounds for delivering active agents,and particularly biologically or chemically active agents. Thesecompounds are used as carriers to facilitate the delivery of a cargo toa target. The carrier compounds are well suited to form non-covalentmixtures with biologically-active agents for oral administration toanimals. Methods for the preparation administration of such compositionsare also disclosed.

BACKGROUND OF THE INVENTION

Conventional means for delivering active agents are often severelylimited by biological, chemical, and physical barriers. Typically, thesebarriers are imposed by the environment through which delivery occurs,the environment of the target for delivery, or the target itself.Biologically or chemically active agents are particularly vulnerable tosuch barriers.

For example in the delivery to animals of biologically active orchemically active pharmacological and therapeutic agents, barriers areimposed by the body. Examples of physical barriers are the skin andvarious organ membranes that must be traversed before reaching a target.Chemical barriers include, but are not limited to, pH variations, lipidbi-layers, and degrading enzymes.

These barriers are of particular significance in the design of oraldelivery systems. Oral delivery of many biologically or chemicallyactive agents would be the route of choice for administration to animalsif not for biological, chemical, and physical barriers such as varyingpH in the gastro-intestinal (GI) tract, powerful digestive enzymes, andactive agent impermeable gastro-intestinal membranes. Among the numerousagents which are not typically amenable to oral administration arebiologically or chemically active peptides, such as calcitonin andinsulin; polysaccharides, and in particular mucopolysaccharidesincluding, but not limited to, heparin; heparinoids; antibiotics; andother organic substances. These agents are rapidly rendered ineffectiveor are destroyed in the gastro-intestinal tract by acid hydrolysis,enzymes, or the like.

Earlier methods for orally administering vulnerable pharmacologicalagents have relied on the co-administration of adjuvants (e.g.,resorcinols and non-ionic surfactants such as polyoxyethylene oleylether and n-hexadecylpolyethylene ether) to increase artificially thepermeability of the intestinal walls, as well as the co-administrationof enzymatic inhibitors (e.g., pancreatic trypsin inhibitors,diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymaticdegradation.

Liposomes have also been described as drug delivery systems for insulinand heparin. See, for example, U.S. Pat. No. 4,239,754; Patel et al.(1976), FEBS Letters, Vol. 62, pg. 60; and Hashimoto et al. (1979),Endocrinology Japan, Vol. 26, pg. 337.

However, broad spectrum use of such drug delivery systems is precludedbecause: (1) the systems require toxic amounts of adjuvants orinhibitors; (2) suitable low molecular weight cargos, i.e. activeagents, are not available; (3) the systems exhibit poor stability andinadequate shelf life; (4) the systems are difficult to manufacture; (5)the systems fail to protect the active agent (cargo); (6) the systemsadversely alter the active agent; or (7) the systems fail to allow orpromote absorption of the active agent.

More recently, microspheres of artificial polymers of mixed amino acids(proteinoids) have been used to deliver pharmaceuticals. For example,U.S. Pat. No. 4,925,673 describes drug-containing proteinoid microspherecarriers as well as methods for their preparation and use. Theseproteinoid microspheres are useful for the delivery of a number ofactive agents.

There is still a need in the art for simple, inexpensive deliverysystems which are easily prepared and which can deliver a broad range ofactive agents.

SUMMARY OF THE INVENTION

Compounds and compositions which are useful in the delivery of activeagents are provided. These compositions include at least one activeagent, preferably a biologically or chemically active agent, and atleast one of the following compounds 1-193, or salts thereof.

    __________________________________________________________________________    1 #STR1##                                      1                              6-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid                          2 #STR2##                                      2                              8(2-aminobenzoylamino)caprylic acid                                           3 #STR3##                                      3                              8(2-trifluoromethoxy)benzoylamino caprylic acid                               4 #STR4##                                      4                              N-(2-hydroxybenzoyl)isonipecotic acid                                         5 #STR5##                                      5                              4-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid                       6 #STR6##                                      6                              4-[4-(pentafluorobenzoyl)aminophenyl)butyric acid                             7 #STR7##                                      7                              4-[4-(3-anisoyl)aminophenyl)butyric acid                                      8 #STR8##                                      8                              8-(3-anisoyl)aminocapryic acid                                                9 #STR9##                                      9                              4-[4-(phenoxyacetyl)aminophenyl)butyric acid                                  0 #STR10##                                    10                              4-(4-(2-nitrobenzenesulfonyl)aminophenyl)butyric acid                         1 #STR11##                                    11                              8-(2-nitrobenzenesulfonyl)aminocaprylic acid                                  2 #STR12##                                    12                              6-(4-(salicyloyl)aminophenyl)hexanoic acid                                    3 #STR13##                                    13                              8-(2-methoxylbenzoyl)amino caprylic acid                                      4 #STR14##                                    14                              2-[4-Salicyloylamino)phenyl]ethyl methyl sulfone                              5 #STR15##                                    15                              1-Salicyloyl-2-succinyl hydrazide                                             6 #STR16##                                    16                              3-(4-(2,5-dimethoxycinnamoyl)aminophenyl)propionic acid                       7 #STR17##                                    17                              4-(4-(2,5-dimethoxycinnamoyl)aminophenyl)butyric acid                         8 #STR18##                                    18                              1-salicyloyl-2-glutaryl hydrazide                                             9 #STR19##                                    19                              Succinyl-4-aminosalicylic acid                                                0 #STR20##                                    20                              8-(Phenoxyacetylamino)caprylic acid                                           1 #STR21##                                    21                              8-(2-pyrazinecarbonyl)aminocaprylic acid                                      2 #STR22##                                    22                              4-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid                             3 #STR23##                                    23                              6-(4-(N-2-Nitrobenzoyl)aminophenyl)hexanoic acid                              4 #STR24##                                    24                              6-(4-(N-2-aminobenzoyl)aminophenyl)hexanoic acid                              5 #STR25##                                    25                              4-(4-(2-(3-carboxyl)pyrazinecarboxyl)aminophenyl)butyric acid                 6 #STR26##                                    26                              4(2-Nirtobenzoyl)aminophenylsuccinic acid                                     7 #STR27##                                    27                              8-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid                             8 #STR28##                                    28                              9 #STR29##                                    29                              8-(Benzylcarbonylamino)caprylic acid                                          0 #STR30##                                    30                              8-(phenylcarbonylamino)caprylic acid                                          1 #STR31##                                    31                              2-[4-(2-Methoxybenzoylamino)phenyl]ethyl H.sub.2 PO.sub.4                     2 #STR32##                                    32                              1-salicyloyl-2-suberyl hydrazide                                              3 #STR33##                                    33                              4-(4-benzyloxycarbonylaminophenyl)butyric acid                                4 #STR34##                                    34                              4-(4-(2-hydroxynicotinoyl)aminophenyl)butyric acid                            5 #STR35##                                    35                              9-Salicyloylaminononanic acid                                                 6 #STR36##                                    36                              4-(4-phenyloxycarbonylaminophenyl)butyric acid                                7 #STR37##                                    37                              3-(2-methoxybenzoylamino)-1-propanol                                          8 #STR38##                                    38                              8-(2-Hydroxynicotinoyl)aminocaprylic acid                                     9 #STR39##                                    39                              6-(2-methoxybenzoyl)amino nicotinic acid                                      0 #STR40##                                    40                              salicyloylglycine                                                             1 #STR41##                                    41                              4-(1-(2-pyrimidyl)piperazinoyl)butyric acid                                   2 #STR42##                                    42                              8-(chromone-3-carbonyl)aminocaprylic aicd                                     3 #STR43##                                    43                              8-(vinylbnezoyl)aminocaprylic acid                                            4 #STR44##                                    44                              4-(4-(chromone-3-carbonyl)aminophenyl)butyric acid                            5 #STR45##                                    45                              8-cinnamoylaminocaprylic aicd                                                 6 #STR46##                                    46                              5-(N-salicyloylamino)valeric acid                                             7 #STR47##                                    47                              9-(2-hydroxybenzamido)nonanic acid                                            8 #STR48##                                    48                              N-(4-salicyloylamino)-6-caproic acid                                          9 #STR49##                                    49                              4'-flavonic acid                                                              0 #STR50##                                    50                              11-cinnamoylaminoundecanoic acid                                              1 #STR51##                                    51                              4-octanoylamino-3-hydroxybenzoic acid                                         2 #STR52##                                    52                              (3Phenyl2,3dihydroxypropanoyl)8aminocaprylic acid                             3 #STR53##                                    53                              8-[N-(3-coumarincarbonyl)]aminocaprylic acid                                  4 #STR54##                                    54                              8-[N-(4-chlorobenzoyl)]aminocaprylic acid                                     5 #STR55##                                    55                              8-[N-3-fluorobenzoyl)]aminocaprylic acid                                      6 #STR56##                                    56                              8-(N-2,5-Dihydroxybenzoyl)aminocaprylic acid                                  7 #STR57##                                    57                              8-(N-2,3-Dimethoxybenzoyl)aminocaprylic acid                                  8 #STR58##                                    58                              8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid                                  9 #STR59##                                    59                              8-(N-2,5-Dimethoxybenzoyl)aminocaprylic acid                                  8 #STR60##                                                                    8-(N-3,5-Diacetlyoxybenzoyl)aminocaprylic acid                                0 #STR61##                                    61                              8-(N-4-Hydroxybenzoyl)aminocaprylic aicd (dimer)                              1 #STR62##                                    62                              8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid                                  9 #STR63##                                                                    10-(N-2-Methoxyanilino)sebalic acid                                           2 #STR64##                                    64                              10-(N-2-hydrosesanilino)sebalic acid                                          0 #STR65##                                                                    2-Methoxybenzeneaminodecanoic acid                                            3 #STR66##                                    66                              8-(N-benzoyl)aminocaprylic acid                                               4 #STR67##                                    67                              8-(N-2-Hydroxy-4-methoxybenzoyl)aminocaprylic acid                            5 #STR68##                                    68                              8-[N-(4-fluorobenzoyl)]aminocaprylic acid                                     6 #STR69##                                    69                              8-[N-(3-bromobenzoyl)]aminocaprylic acid                                      7 #STR70##                                    70                              8-(4-(1,2-dihydroxyethyl)benzoyl)aminocaprylic acid                           8 #STR71##                                    71                              8-[N-(4-bromobenzoyl)]aminocaprylic acid                                      9 #STR72##                                    72                              8-[N-(4-iodobenzoyl)]aminocaprylic acid                                       0 #STR73##                                    73                              4-{4-[N-(2-iodobenzoyl)aminophenyl]}butyric acid                              1 #STR74##                                    74                              4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid                      2 #STR75##                                    75                              4-(4-(2,4-dimethoxybenzoyl)aminophenyl)butyric acid                           3 #STR76##                                    76                              4-(o-anisoyl)aminophenylacetic acid                                           4 #STR77##                                    77                              3-[4-(2,4-dimethoxybenzoyl) aminophenyl]propionic acid                        5 #STR78##                                    78                              4-{4-[N-(4-iodobenzoyl)]amionphenyl}butyric acid                              6 #STR79##                                    79                              3-[4-(2,3-dimethoxybenzoyl) aminophenyl]propionic acid                        7 #STR80##                                    80                              4{4-[N-2-bromobenzoyl)]aminophenyl}butyric acid                               8 #STR81##                                    81                              4{-[N-3-bromobenzoyl) aminophenyl}butyric acid                                9 #STR82##                                    82                              8-(N-3,5 Dihydroxybenzoyl)aminocaprylic acid                                  0 #STR83##                                    83                              8-(N-3,5-Dimethoxy 4-hydroxybenzoyl)aminocaprylic acid                        1 #STR84##                                    84                              8-(N-2-6-Dimethoxybenzoyl)aminocaprylic acid                                  2 #STR85##                                    85                              4-{4-[N-(4-bromobenzoyl)aminophenyl]}butyric acid                             3 #STR86##                                    86                              8-(2-hydroxy-4-chlorobenzoyl)aminocaprylic acid                               4 #STR87##                                    87                              8-(N-2,6-Dihydroxybenzoyl)aminocaprylic acid                                  5 #STR88##                                    88                              8-(N-2-Hydroxy6-methoxybenzoyl)aminocaprylic acid                             6 #STR89##                                    89                              8-(5-chloro-o-anisoyl)aminocaprylic acid                                      7 #STR90##                                    90                              4-(4-(2,3-dimethoxybenzoyl)aminophenyl)butyric acid                           8 #STR91##                                    91                              4-(4-(5-chloro-o-anisoyl)aminophenyl)butyric acid                             9 #STR92##                                    92                              4-(4-(4-chloro-o-aniosyl)aminophenyl)butyric acid                             0 #STR93##                                    93                              8-(4-chloro-o-aniosyl)aminocaprylic acid                                      1 #STR94##                                    94                              3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid                         2 #STR95##                                    95                              4-{N-[4-(3-iodobenzoyl)aminophenyl]}butyric acid                              3 #STR96##                                    96                              7-cinnamoylaminoheptanoic acid                                                4 #STR97##                                    97                              8-N-(3-iodobenzoyl)aminocaprylic acid                                         5 #STR98##                                    98                              8-N-(4-methoxy-3-nitrobenzoyl)aminocaprylic acid                              6 #STR99##                                    99                              8-N-(2-methoxy-4-nitorbenzoyl)aminocaprylic acid                              7 #STR100##                                   100                             4-{N-[4-(2-methoxy-4-nitrobenzoyl)aminophenyl]}butyric acid                   8 #STR101##                                   101                             4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid                           9 #STR102##                                   102                             8-(N-2-hydroxy-5-bromobenzoyl)aminocaprylic acid                              0 #STR103##                                   103                             3-Indolebutyric acid                                                          1 #STR104##                                   104                             2 #STR105##                                   105                             3 #STR106##                                   106                             4 #STR107##                                   107                             4-(4-(2,6-dimethoxybenzoyl)aminophenylbutyric acid                            5 #STR108##                                   108                             4-[4-N-(4-methoxy-3-nitrobenzoyl)aminophenyl]butyric acid                     6 #STR109##                                   109                             8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid                             7 #STR110##                                   110                             8-(N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid                               8 #STR111##                                   111                             8-(3-hydroxy-3-naphthoyl)aminocaprylic acid                                   9 #STR112##                                   112                             8-(N-2-hydroxy-4-nitorbenzoyl)aminocaprylic acid                              0 #STR113##                                   113                             4-[N-(2-hydroxy-4-bromobenzoyl)aminophenyl]butyric acid                       1 #STR114##                                   114                             8-(N-2,3-Dihydroxybenzoyl)aminocaprylic acid                                  2 #STR115##                                   115                             8-(N-3-methylsalicyloyl)aminocaprylic acid                                    3 #STR116##                                   116                             8-(N-5-methylsalicyloyl)aminocaprylic acid                                    4 #STR117##                                   117                             9-(cinnamoylamino)nonanoic acid                                               5 #STR118##                                   118                             4-(4-(2-chloro-5-nitrobenzoyl)aminophenyl)butyric acid                        6 #STR119##                                   119                             4-{-[N-(2-hydroxy-5-iodobenzoyl)]aminophenyl}butyric acid                     7 #STR120##                                   120                             N-2-nitrophenyl-N'-(8-octanoic acid) urea                                     8 #STR121##                                   121                             N-(2-methoxy-5-nitrophenyl) sebecoyl amide acid                               9 #STR122##                                   122                             8-[N-(2-acetoxy-3,5-dichlorobenzoyl)]aminocaprylic acid                       0 #STR123##                                   123                             8-[N-(2-acetoxy-3,5-dibromobenzoyl)]aminocaprylic acid                        1 #STR124##                                   124                             8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid                              2 #STR125##                                   125                             1 #STR126##                                   126                             8-N-(4-hydroxy-3-nitrobenzoyl)caprylic acid                                   3 #STR127##                                   127                             4-(4-Salicyloylaminophenyl)-4-oxobutyric acid                                 4 #STR128##                                   128                             12-cinnamoyldodecanoic acid                                                   5 #STR129##                                   129                             4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}butyric acid                       6 #STR130##                                   130                             8-(4-chloro-3-nitrobenzoyl)aminocaprylic acid                                 7 #STR131##                                   131                             8-(2-chloronicotinoyl)aminocaprylic acid                                      8 #STR132##                                   132                             8-(2-chloro-5-nitrobenzoyl)aminocaprylic acid                                 9 #STR133##                                   133                             4-(4-phthalimidophenyl)butyric acid                                           0 #STR134##                                   134                             4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}propanoic acid                     1 #STR135##                                   135                             3-(4-(2,6-dimethoxybenzoyl)aminophenyl)propionic acid                         2 #STR136##                                   136                             8-(N-2-hydroxy-3,5-diiodobenzoyl)aminocaprylic acid                           3 #STR137##                                   137                             8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid                              4 #STR138##                                   138                             8-(2-(1,2-dihydroisoindole-1-one))octanoic acid                               5 #STR139##                                   139                             8-(N-2-hydroxy-2-naphthoyl)aminocaprylic acid                                 6 #STR140##                                   140                             8-(phthalimido)caprylic acid                                                  7 #STR141##                                   141                             10-(4-chloro-2-hydroxyanilino)sebacic acid monoamide                          8 #STR142##                                   142                             6-(anisoyl)aminocaproic acid                                                  9 #STR143##                                   143                             4-(4-(4-chloro-3-nitrobenzoyl)aminophenyl)butyric acid                        0 #STR144##                                   144                             11-N-(1-hydroxy-2-naphthoyl)aminoundecanoic acid                              1 #STR145##                                   145                             Bis(N-2carboxylphenyl-N-(N'-8-octanoic acid)oxalyl diamide                    2 #STR146##                                   146                             2-[2-N-(2-chlorobenzoyl)aminoethoxy]ethanol                                   3 #STR147##                                   147                             2-[2-N-(4-chlorobenzoyl)aminoethoxy]ethanol                                   4 #STR148##                                   148                             4-(2-methoxybenzoyl)amino 3-carboxysulfoxide                                  5 #STR149##                                   149                             4-(2-methoxybenzoyl)amino 3-carboxypropylsulfone                              2 #STR150##                                   150                             4-(4-(3-hydroxyphthalimido)phenyl)butyric acid                                6 #STR151##                                   151                             2-[2-N-(2-methoxybenzoyl)aminoethoxy)]ethanol                                 7 #STR152##                                   152                             2-[2-N-(3-chlorobenzoyl)aminoethoxy)]ethanol                                  8 #STR153##                                   153                             Bis(N-2-carboxyphenyl-N-(N'-3(4-aminophenyl)propionic acid)ureal)oxaylyl      diamide                                                                       9 #STR154##                                   154                             trans-4-(2-amiobenzamidomethyl)cyclohexamecarboxylic acid                     0 #STR155##                                   155                             11-N-(3,5-dichloro-2-hydroxybenzoyl)aminoundecanoic acid                      1 #STR156##                                   156                             2-[N-(2-bromobenzoyl)aminoethoxyl]ethanol                                     2 #STR157##                                   157                             7-N-(3,5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid                        3 #STR158##                                   158                             N-[3,5-dichloro-2-hydroxybenzoyl-4(4-aminophenyl)]butyric acid                4 #STR159##                                   159                             trans-4-(N-salicyloylaminomethyl)cyclohexane carboxylic acid                  5 #STR160##                                   160                             N-[3,5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)]propionic acid             6 #STR161##                                   161                             12-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecanoic acid                      7 #STR162##                                   162                             N-(2-hydroxy-4-carboxy)-6-heptenamide                                         8 #STR163##                                   163                             N-(2-bromobenzoyl)morpholine                                                  9 #STR164##                                   164                             8-N-cylcohexanoylaminocaprylic acid                                           0 #STR165##                                   165                             2-[N-(2-iodobenzoyl)aminoethoxyl]ethanol                                      1 #STR166##                                   166                             5-(4-chloro-2-hydroxyanilinocarbonyl)valeric acid                             2 #STR167##                                   167                             8-(2-hydroxyphenoxy)-aminocaprylic acid                                       3 #STR168##                                   168                             N-Salicoyl-5-(3-aminophenyl)valerica acid                                     4 #STR169##                                   169                             4-(4-(2-ethoxylbenzoyl)aminophenyl)butyric acid                               5 #STR170##                                   170                             9-[2-(3-hydroxy)pyridylaminocarbonyl]nonanic acid                             6 #STR171##                                   171                             7-(2-hydroxyphenoxyacetyl)aminocaprylic acid                                  7 #STR172##                                   172                             2-[N-(2-hydroxybenzoylamino)ethoxyl]ethanol                                   8 #STR173##                                   173                             4-[N-(3,5-dichloro-2-hydroxybenzoyl)]aminophenylacetic acid                   9 #STR174##                                   174                             8-(2-hydroxy-5-chloroanilinocarbonyl)octanoic acid                            0 #STR175##                                   175                             N-salicoyl-5-(4-aminophenyl)valeric acid                                      1 #STR176##                                   176                             9-(2-hydroxy-5-methylanilinocarbonyl)nonanoic acid                            2 #STR177##                                   177                             5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid                             3 #STR178##                                   178                             8-(pentafluorobenzoyl)aminocaprylic acid                                      4 #STR179##                                   179                             3-(3-(salicyloyl)aminophenyl)propionic acid                                   5 #STR180##                                   180                             8-(2-ethoxybenzoyl)aminocaprylic acid                                         6 #STR181##                                   181                             4-(4-(2-Dimethylamino benzoic)aminophenyl)butyric acid                        7 #STR182##                                   182                             8-(3-Phenoxylpropionylamino)caprylic acid                                     8 #STR183##                                   183                             4-(salicyloyl)aminophenylethyltetrazole                                       9 #STR184##                                   184                             8(-(4(N-Saliciloyl-4aminophenyl)butyric)aminocaprylic acid [sic]              0 #STR185##                                   185                             4-(4-(N-(2-Fluorocinnamoyl))aminophenyl) butyric                              1 #STR186##                                   186                             4-(4-(N-8(N-Salicyloyl)aminocaprylic)aminophenyl)butyric acid                 2 #STR187##                                   187                             8-(p-anisoyl)aminocaprylic acid                                               3 #STR188##                                   188                             8-(4-Hydroxybenzoyl)aminocaprylic acid                                        4 #STR189##                                   189                             8-(3-Hydroxybenzoyl)aminocaprylic acid                                        3 #STR190##                                   190                             8-(3,4,5-Trimethoxybenzoyl)aminocaprylic acid                                 5 #STR191##                                   191                             8-(N-4-Methylsalicyloyl)aminocaprillic acid [sic]                             6 #STR192##                                   192                             N-10-(2-hydroxy-5-nitoranilino)decanoic acid                                  7 #STR193##                                   193                             4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid                             __________________________________________________________________________

Compositions comprising the carrier compounds discussed above and activeagents are effective in delivering active agents to selected biologicalsystems.

DETAILED DESCRIPTION OF THE INVENTION

The specific compositions of the present invention include an activeagent and a carrier. These compositions may be used to deliver variousactive agents through various biological, chemical, and physicalbarriers and are particularly suited for delivering active agents whichare subject to environmental degradation. The compositions of thesubject invention are particularly useful for delivering oradministering biologically or chemically active agents to any animalssuch as birds including, but not limited to, chickens; mammals, such asprimates and particularly humans; and insects.

Other advantages of the present invention include the use of easy toprepare, inexpensive raw materials. The compositions and the formulationmethods of the present invention are cost effective, simple to perform,and amenable to industrial scale up for commercial production.

Subcutaneous, sublingual, and intranasal coadministration of an activeagent, such as, for example, recombinant human growth hormone (rhGH);salmon calcitonin; heparin, including, but not limited to, low molecularweight heparin; parathyroid hormone; and compounds in compositions asdescribed herein result in an increased bioavailability of the activeagent compared to administration of the active agent alone.

Active Agents

Active agents suitable for use in the present invention includebiologically or chemically active agents, chemically active agents,including, but not limited to, fragrances, as well as other activeagents such as, for example, cosmetics.

Biologically or chemically active agents include, but are not limitedto, pesticides, pharmacological agents, and therapeutic agents. Forexample, biologically or chemically active agents suitable for use inthe present invention include, but are not limited to, peptides, andparticularly small peptides; hormones, and particularly hormones whichby themselves do not or only a fraction of the administered dose passesthrough the gastro-intestinal mucosa and/or are susceptible to chemicalcleavage by acids and enzymes in the gastro-intestinal tract;polysaccharides, and particularly mixtures of muco-polysaccharides;carbohydrates; lipids; or any combination thereof. Further examplesinclude, but are not limited to, human growth hormones; bovine growthhormones; growth releasing hormones; interferons; interleukin-1;insulin; heparin, and particularly low molecular weight heparin;calcitonin; erythropoietin; atrial naturetic factor; antigens;monoclonal antibodies; somatostatin; adrenocorticotropin, gonadotropinreleasing hormone; oxytocin; vasopressin; cromolyn sodium (sodium ordisodium chromoglycate); vancomycin; desferrioxamine (DFO); parathyroidhormone anti-microbials, including, but not limited to anti-fungalagents; or any combination thereof.

Carriers

Although compounds 1-193 above have been found to act as carriers forthe oral delivery of biologically or chemically active agents, specialmention is made of compounds 9, 35, 64, 67, 79, 102, 109, 111, 117, 122,136, and 141, above.

Properties of compounds 1-193 are listed in Table 1, below.

                                      TABLE 1                                     __________________________________________________________________________    Carrier Properties                                                            Anal. Calculated For                                                                             Found         Melting                                      Compound                                                                            C  H   N  S  C   H  N   S  Point (° C.)                          __________________________________________________________________________    1     48.8                                                                             4.70                                                                              4.40  48.81                                                                             4.64                                                                             4.39                                                2     64.73                                                                            7.97                                                                              10.06 64.54                                                                             7.81                                                                             10.19                                               3     55.33                                                                            5.80                                                                              4.03  55.40                                                                             5.79                                                                             3.96   69-71                                        4     62.64                                                                            6.06                                                                              5.62  62.75                                                                             6.08                                                                             5.51   151-154                                      5     65.16                                                                            6.11                                                                              13.40 65.29                                                                             6.03                                                                             13.29  144-145                                      6     54.70                                                                            3.24                                                                              3.75  54.29                                                                             3.24                                                                             3.54   165-169                                      7     69.00                                                                            6.11                                                                              4.47  69.09                                                                             6.24                                                                             4.43   126-129                                      8     65.51                                                                            7.90                                                                              4.78  65.60                                                                             8.25                                                                             4.83   89-90                                        9     68.99                                                                            6.11                                                                              4.47  69.01                                                                             6.08                                                                             4.47   104-107                                      10    52.74                                                                            4.42                                                                              7.69  52.91                                                                             4.45                                                                             7.49   142-145                                      11    48.83                                                                            5.85                                                                              8.14  48.95                                                                             5.89                                                                             8.02   120-122                                      12    69.71                                                                            6.47                                                                              4.28  69.56                                                                             6.47                                                                             4.38   144-146                                      13    65.51                                                                            7.90                                                                              4.77  65.23                                                                             7.88                                                                             4.72   72.5-74.5                                    14    60.17                                                                            5.36                                                                              4.39                                                                             10.04                                                                            60.09                                                                             5.36                                                                             4.35                                                                              9.99                                                                             155-156                                      15    52.38                                                                            4.79                                                                              11.11 52.45                                                                             4.94                                                                             11.08  220-222                                      16    67.60                                                                            5.95                                                                              3.94  67.34                                                                             6.01                                                                             3.91   219-222                                      17    68.09                                                                            6.53                                                                              3.78  67.77                                                                             6.24                                                                             3.81   130-133                                      18    54.13                                                                            5.30                                                                              10.52 54.12                                                                             5.24                                                                             10.54  192.5-195.5                                  19    55.26                                                                            4.21                                                                              7.16  54.48                                                                             4.32                                                                             6.86   >280 dec                                     20    65.51                                                                            7.90                                                                              4.77  65.52                                                                             7.90                                                                             4.77   75-80                                        21    58.85                                                                            7.21                                                                              15.84 58.86                                                                             7.16                                                                             15.69  120-122                                      22    63.15                                                                            5.30                                                                              14.73 63.30                                                                             5.43                                                                             14.18  197-201                                      23    64.04                                                                            5.66                                                                              7.86  64.17                                                                             5.67                                                                             7.75   188-190                                      24    69.91                                                                            6.88                                                                              8.46  69.98                                                                             6.79                                                                             8.58   131-134                                      25    58.36                                                                            4.56                                                                              12.76 58.20                                                                             4.63                                                                             12.61  138-141                                      26    56.98                                                                            3.94                                                                              7.82  56.39                                                                             3.92                                                                             7.74   221-223                                      27    55.33                                                                            5.80                                                                              4.03  55.47                                                                             6.10                                                                             4.04   70-72                                        28                                                                            29    65.74                                                                            7.58                                                                              4.79  65.51                                                                             7.89                                                                             4.78   52-55                                        30    64.50                                                                            7.57                                                                              5.02  64.07                                                                             7.81                                                                             5.40   70-74                                        31    54.70                                                                            5.17                                                                              3.99  54.50                                                                             4.99                                                                             3.95   173-174                                      32    58.63                                                                            5.94                                                                              9.12  58.73                                                                             6.20                                                                             10.34  125-129                                      33    69.00                                                                            6.10                                                                              4.47  69.18                                                                             6.08                                                                             4.54   100-102                                      34    63.99                                                                            5.37                                                                              9.33  63.46                                                                             5.35                                                                             9.06   218-221c                                     35    65.5                                                                             7.90                                                                              4.78  65.37                                                                             8.00                                                                             4.66   96-97C                                       36    68.22                                                                            5.72                                                                              4.68  67.88                                                                             5.65                                                                             4.55   134-137                                      37    63.14                                                                            7.23                                                                              6.69  63.15                                                                             7.29                                                                             6.58   53.5-56                                      38    60.00                                                                            7.14                                                                              10.00 59.78                                                                             7.31                                                                             9.94   135-138                                      39    61.67                                                                            4.41                                                                              10.29 61.69                                                                             4.41                                                                             10.12  >225                                         40    55.39                                                                            4.65                                                                              7.18  55.52                                                                             4.77                                                                             7.30   162.5-166                                    41    56.10                                                                            6.52                                                                              20.14 55.66                                                                             6.71                                                                             19.69  129-131                                      42    65.24                                                                            6.39                                                                              4.23  65.42                                                                             6.16                                                                             3.78   130-133.5                                    43    70.59                                                                            7.96                                                                              4.84  70.35                                                                             8.13                                                                             4.79   111-113                                      44    68.37                                                                            4.88                                                                              3.99  68.61                                                                             4.89                                                                             3.79   120-123                                      45    70.59                                                                            7.96                                                                              4.84  70.48                                                                             7.97                                                                             4.71   108-110                                      46    60.75                                                                            6.37                                                                              5.90  60.97                                                                             6.18                                                                             5.80   100.5-103                                    47    64.50                                                                            7.57                                                                              5.02  64.42                                                                             7.58                                                                             5.01   97-100                                       48    64.86                                                                            5.98                                                                              7.56  64.50                                                                             6.01                                                                             7.52   165-169                                      49    72.18                                                                            3.76                                                                              0.00  72.13                                                                             3.84                                                                             0.00   >225                                         50    72.51                                                                            8.76                                                                              4.23  72.39                                                                             8.84                                                                             4.12   120-122                                      51    64.50                                                                            7.58                                                                              5.01  64.75                                                                             7.65                                                                             4.69   200.5-204                                    52       7.74                                                                              4.33      7.82                                                                             4.30   88-89                                        53    65.24                                                                            6.39                                                                              4.23  65.15                                                                             6.46                                                                             4.23   93-97                                        54    60.49                                                                            6.77                                                                              4.70  60.54                                                                             6.76                                                                             4.65   114-116                                      55    64.04                                                                            7.17                                                                              4.98  63.90                                                                             7.11                                                                             4.93   105-106                                      56    61.00                                                                            7.17                                                                              4.74  60.49                                                                             6.92                                                                             4.65   146-148                                      57    63.14                                                                            7.79                                                                              4.33  63.22                                                                             7.82                                                                             4.36   59-61                                        58    63.14                                                                            7.79                                                                              4.33  63.17                                                                             7.86                                                                             4.26   102-104                                      59    63.14                                                                            7.79                                                                              4.33  63.35                                                                             7.68                                                                             4.20   89-90                                        60    60.15                                                                            6.64                                                                              3.69  59.84                                                                             6.66                                                                             3.64   112-113                                      61    65.53                                                                            8.85                                                                              6.65  65.34                                                                             8.73                                                                             6.67   89-92                                        62    61.00                                                                            7.17                                                                              4.74  60.94                                                                             7.12                                                                             4.49   104-108                                      63    66.43                                                                            8.20                                                                              4.56  66.29                                                                             8.23                                                                             4.36   77-78                                        64    65.51                                                                            7.90                                                                              4.77  65.52                                                                             8.06                                                                             4.54   97-98                                        65    69.59                                                                            9.28                                                                              4.77  69.64                                                                             9.35                                                                             4.86   62-65                                        66    68.41                                                                            8.04                                                                              5.32  68.41                                                                             8.06                                                                             5.28   88-89                                        67    62.12                                                                            7.49                                                                              4.53  61.94                                                                             7.45                                                                             4.43   98-99                                        68    64.04                                                                            7.17                                                                              4.98  64.07                                                                             7.16                                                                             4.95   106-107                                      69    52.64                                                                            5.89                                                                              4.09  52.63                                                                             5.85                                                                             4.03   109-110                                      70    63.15                                                                            7.74                                                                              4.33  63.26                                                                             7.90                                                                             4.14   97-100                                       71    52.64                                                                            5.89                                                                              4.09  52.67                                                                             5.99                                                                             3.97   114-115                                      72    46.31                                                                            5.18                                                                              3.61  46.25                                                                             4.86                                                                             3.52   143-144                                      73    49.89                                                                            3.94                                                                              3.42  49.92                                                                             3.85                                                                             3.39   170-171                                      74    72.19                                                                            5.48                                                                              4.01  71.51                                                                             5.33                                                                             3.75   180                                          75    66.46                                                                            6.16                                                                              4.08  66.47                                                                             6.26                                                                             4.06   168.5-171                                    76    67.37                                                                            5.26                                                                              4.91  67.31                                                                             5.25                                                                             5.07   130-133                                      77    65.65                                                                            5.78                                                                              4.26  65.49                                                                             6.04                                                                             4.26   179-183                                      78    49.89                                                                            3.94                                                                              3.42  49.8                                                                              3.71                                                                             3.29   237-238                                      79    65.65                                                                            5.78                                                                              4.26  65.21                                                                             6.05                                                                             4.24   156-158                                      80    56.38                                                                            4.45                                                                              3.87  56.4                                                                              4.21                                                                             3.91   130-131                                      81    56.38                                                                            4.45                                                                              3.87  56.46                                                                             4.5                                                                              3.84   197-198                                      82    56.6                                                                             7.49                                                                              4.4   56.3                                                                              7.49                                                                             4.14   58-62                                        83    57.03                                                                            8.2 3.91  57.17                                                                             7.8                                                                              3.7    138-140                                      84    57.58                                                                            7.11                                                                              3.95  57.52                                                                             7.7                                                                              3.94                                                85    56.38                                                                            4.45                                                                              3.87  56.31                                                                             4.25                                                                             3.64   230-231                                      86    57.42                                                                            6.42                                                                              4.46  57.14                                                                             6.45                                                                             4.2    116-117                                      87    61 7.17                                                                              4.74  61.18                                                                             7.05                                                                             4.65   108-109                                      88    62.12                                                                            7.49                                                                              4.53  62.34                                                                             7.21                                                                             4.39   107-109                                      89    58.63                                                                            6.76                                                                              4.27  58.53                                                                             6.81                                                                             4.2    117-118                                      90    66.46                                                                            6.16                                                                              4.08  66.18                                                                             6.15                                                                             3.84   100-104                                      91    62.16                                                                            5.21                                                                              4.03  61.93                                                                             4.97                                                                             3.86   183-185                                      92    62.16                                                                            5.21                                                                              4.03  62.2                                                                              5.14                                                                             3.98   167-170                                      93    58.63                                                                            6.76                                                                              4.27  58.64                                                                             6.83                                                                             4.19   106-108                                      94    65.65                                                                            5.81                                                                              4.25  65.56                                                                             5.64                                                                             4.2    153-156                                      95    49.89                                                                            3.94                                                                              3.42  49.9                                                                              3.81                                                                             3.18   216-217                                      96    69.82                                                                            7.64                                                                              5.09  69.91                                                                             7.66                                                                             5.02   129-131                                      97    46.31                                                                            5.18                                                                              3.61  46.54                                                                             4.95                                                                             3.64   122-123                                      98    56.8                                                                             6.55                                                                              8.28  56.69                                                                             6.67                                                                             8.1                                                 99    56.8                                                                             6.55                                                                              8.28  57.37                                                                             6.57                                                                             8.33   117-118                                      100   60.33                                                                            5.06                                                                              7.82  59.98                                                                             4.97                                                                             7.67   207-209                                      101   66.46                                                                            6.16                                                                              4.08  66.37                                                                             6.32                                                                             3.96   126-128                                      102   50.29                                                                            5.63                                                                              3.91  50.14                                                                             5.7                                                                              3.76   129-131                                      103   70.93                                                                            5.95                                                                              6.89  70.94                                                                             6.44                                                                             6.89                                                104   65.84                                                                            6.14                                                                              8.53  65.94                                                                             6.19                                                                             8.54   228-231                                      105   64.96                                                                            5.77                                                                              8.91  64.89                                                                             5.82                                                                             8.82                                                106   66.65                                                                            6.48                                                                              8.18  66.39                                                                             6.49                                                                             8.05   140-142                                      107   66.47                                                                            6.12                                                                              4.07  66.5                                                                              6.26                                                                             4.08   140-142                                      108   60.33                                                                            5.06                                                                              7.82  60.32                                                                             4.99                                                                             7.78   150-151                                      109   57.41                                                                            6.42                                                                              4.46  57.07                                                                             6.44                                                                             4.39   121-123                                      110   44.46                                                                            4.97                                                                              3.46                133-135                                      111   69.28                                                                            7.03                                                                              4.25  68.86                                                                             7.07                                                                             4.11   147-149                                      112   55.55                                                                            6.22                                                                              8.64  55.27                                                                             5.99                                                                             8.5    120-121                                      113   53.99                                                                            4.26                                                                              3.7   53.98                                                                             4.25                                                                             3.63   210 decom                                    114   57.49                                                                            7.39                                                                              4.74  57.72                                                                             7.57                                                                             4.43   80-83                                        115   65.5                                                                             7.9 4.77  64.97                                                                             7.79                                                                             4.75   90-92                                        116   65.5                                                                             7.9 4.77  65.11                                                                             8.03                                                                             4.71   125-127                                      117   71.26                                                                            8.3 4.2   70.6                                                                              7.89                                                                             4.83   94-96                                        118   56.29                                                                            4.17                                                                              7.72  56.23                                                                             4.01                                                                             7.6    173-175                                      119   47.89                                                                            3.81                                                                              3.29  47.52                                                                             3.71                                                                             3.16   236-237                                      120   55.7                                                                             6.55                                                                              13    55.71                                                                             6.58                                                                             13.05  123-5                                        121   57.98                                                                            5.81                                                                              7.95  57.9                                                                              7.11                                                                             7.82   131-133                                      122   51.74                                                                            5.5 4.02  51.41                                                                             5.43                                                                             3.61   118-119.5                                    123   41.22                                                                            4.38                                                                              3.2   41.45                                                                             4.36                                                                             2.94   143-144.5                                    124   57.06                                                                            6.06                                                                              4.44  57.02                                                                             6.12                                                                             4.35   57-58                                        125   61.18                                                                            4.83                                                                              4.2   60.71                                                                             4.76                                                                             3.89   214 decom                                    126   55.55                                                                            6.22                                                                              8.64  55.4                                                                              6.24                                                                             8.53   150-151                                      127   65.17                                                                            4.83                                                                              4.47  65.27                                                                             4.87                                                                             4.48   208-209                                      128   73.03                                                                            8.99                                                                              4.06  72.92                                                                             9.36                                                                             4.1    99-101                                       129   72.25                                                                            5.44                                                                              4     72.14                                                                             5.24                                                                             4.01   216-217                                      130   52.56                                                                            5.58                                                                              8.17  52.66                                                                             5.44                                                                             8.21   96-100                                       131   56.28                                                                            6.41                                                                              9.38  56.32                                                                             6.42                                                                             9.28   98-100                                       132   52.56                                                                            5.58                                                                              8.17  52.46                                                                             5.65                                                                             7.86   150-153                                      133   69.89                                                                            4.89                                                                              4.53  69.64                                                                             5  4.54   136-9                                        134   71.68                                                                            5.2 4.2   71.24                                                                             5.1                                                                              4.13   251-253                                      135   65.64                                                                            5.78                                                                              4.25  65.3                                                                              5.91                                                                             4.04   79-83                                        136   33.92                                                                            3.61                                                                              2.64  34.48                                                                             3.84                                                                             2.48   164-165                                      137   57.06                                                                            6.06                                                                              4.44  57.09                                                                             6.17                                                                             4.45   88-89                                        138   69.79                                                                            7.69                                                                              5.09  69.68                                                                             7.78                                                                             5.08   102-3                                        139   69.28                                                                            7.04                                                                              4.25  68.99                                                                             7  4.1    107-108                                      140   66.42                                                                            6.62                                                                              4.84  66.2                                                                              6.49                                                                             4.81   88-9                                         141   58.62                                                                            6.76                                                                              4.27  58.66                                                                             6.93                                                                             4.18   134-135                                      142   63.38                                                                            7.21                                                                              5.28  63.22                                                                             7.28                                                                             5.24   71-73                                        143   56.29                                                                            4.17                                                                              7.72  56.19                                                                             4.04                                                                             7.65   156-160                                      144   71.13                                                                            7.88                                                                              3.77  70.39                                                                             7.91                                                                             3.64   95-97                                        145   58.44                                                                            6.06                                                                              8.02  58.25                                                                             6.38                                                                             7.84   165-8                                        146   54.22                                                                            5.79                                                                              5.75  54.26                                                                             5.65                                                                             5.69   77-78.5                                      147   54.22                                                                            5.79                                                                              5.75  54.21                                                                             5.85                                                                             5.61   80-81                                        148   58.78                                                                            4.93                                                                              40.3  58.64                                                                             4.89                                                                             3.97   172-173                                      149   56.19                                                                            4.72                                                                              3.85  56.31                                                                             4.67                                                                             3.86   177                                          150   66.46                                                                            4.65                                                                              4.31  66.41                                                                             4.56                                                                             4.23   158-160                                      151   58.61                                                                            7.24                                                                              5.69  58.79                                                                             7.35                                                                             5.66                                                152   54.22                                                                            5.79                                                                              5.75  54.21                                                                             5.72                                                                             5.62   54-55                                        153   60.85                                                                            4.25                                                                              7.89  60.27                                                                             4.37                                                                             7.89   >260                                         154   62.5                                                                             7.3 10.14 64.77                                                                             7.27                                                                             9.9    187-190                                      155   55.4                                                                             6.5 3.6   55.56                                                                             6.51                                                                             3.5    114-116                                      156   45.85                                                                            4.9 4.86  46.06                                                                             4.78                                                                             4.71   67-68                                        156   48.8                                                                             4.7 4.4   48.81                                                                             4.64                                                                             4.39   144-146                                      157   50.3                                                                             5.1 4.2   50.25                                                                             5.12                                                                             3.99   141-143                                      158   55.5                                                                             4.1 3.8   55.55                                                                             3.88                                                                             3.75   190-192                                      159   64.97                                                                            6.9 5.05  64.7                                                                              6.82                                                                             5.02   171-174                                      160   54.3                                                                             3.7 4     54.31                                                                             3.58                                                                             3.83   222-224                                      161   56.4                                                                             6.7 3.5   56.69                                                                             6.98                                                                             3.11   76-78                                        162   63.63                                                                            6.47                                                                              5.3   64.76                                                                             6.84                                                                             4.74   188-191                                      163   48.91                                                                            4.48                                                                              5.19  48.89                                                                             4.31                                                                             5.10   88.5-90                                      164   66.66                                                                            10.04                                                                             5.18  66.69                                                                             10.77                                                                            5.16   67.5-70.5                                    165   39.42                                                                            4.21                                                                              4.18  39.19                                                                             4.35                                                                             3.88   oil                                          166   53.05                                                                            5.19                                                                              5.16  53.06                                                                             5.03                                                                             4.86   151-152                                      167   65.53                                                                            7.85                                                                              4.78  65.4                                                                              7.84                                                                             4.57   85-89                                        168   68.99                                                                            6.11                                                                              4.47  68.62                                                                             5.87                                                                             4.49   162-6                                        169   69.71                                                                            6.47                                                                              4.28  69.67                                                                             6.58                                                                             4.50   132.5-135                                    170   61.21                                                                            7.53                                                                              9.52  61.21                                                                             7.68                                                                             9.46   134-135                                      171   62.14                                                                            7.44                                                                              4.53  61.96                                                                             7.52                                                                             4.57   101-104                                      172   58.63                                                                            6.71                                                                              6.22  58.15                                                                             6.83                                                                             6.04                                                173   52.96                                                                            3.26                                                                              4.12  52.96                                                                             3.28                                                                             4.02   225-227                                      174   57.42                                                                            6.42                                                                              4.46  57.3                                                                              6.38                                                                             4.39   119-120                                      175   68.99                                                                            6.11                                                                              4.47  68.84                                                                             6.08                                                                             4.51   131-4                                        176   66.43                                                                            8.2 4.56  66.42                                                                             8.16                                                                             4.51   109-110                                      177   62.14                                                                            6.82                                                                              5.57  61.96                                                                             6.66                                                                             5.52   127-128                                      178   51.00                                                                            4.56                                                                              3.97  51.09                                                                             4.61                                                                             3.93                                                179   67.36                                                                            5.30                                                                              4.90  67.26                                                                             5.24                                                                             4.91   185-186                                      180   66.43                                                                            8.20                                                                              4.56  66.32                                                                             8.60                                                                             5.12   51.5-55                                      181   69.92                                                                            6.79                                                                              8.58  67.02                                                                             6.93                                                                             8.20   81-84                                        182   66.46                                                                            8.14                                                                              4.56  66.43                                                                             8.34                                                                             4.47   82-84                                        183   62.13                                                                            4.89                                                                              22.64 62.05                                                                             4.88                                                                             22.45  271-272                                      184   68.16                                                                            7.32                                                                              6.36  67.73                                                                             7.44                                                                             6.70   114-117                                      185   71.30                                                                            5.98                                                                              5.73  71.10                                                                             5.97                                                                             5.74   146-149                                      186   68.16                                                                            7.32                                                                              6.36  67.94                                                                             7.31                                                                             6.41   105-108                                      187   65.51                                                                            7.90                                                                              4.77  65.35                                                                             7.63                                                                             4.59   102-103                                      188   64.50                                                                            7.58                                                                              5.01  64.19                                                                             7.69                                                                             4.83   133-134                                      189   64.5                                                                             7.58                                                                              5.01  64.5                                                                              7.57                                                                             4.90   116-118                                      190   61.15                                                                            7.71                                                                              3.97  61.27                                                                             7.79                                                                             4.08   124-127                                      191   65.5                                                                             7.9 4.77  65.32                                                                             7.94                                                                             4.7    114-115                                      192   56.77                                                                            6.51                                                                              8.28  56.83                                                                             6.76                                                                             8.21   141-143                                      193   60.29                                                                            4.74                                                                              8.79  60.17                                                                             4.58                                                                             8.74   202-205                                      194   48.8                                                                             4.7 4.4   48.81                                                                             4.64                                                                             4.39   144-146                                      __________________________________________________________________________

These carrier compounds or poly amino acids, and peptides, including theacids, may be used to deliver active agents including, but not limitedto, biologically or chemically active agents such as for example,pharmacological and therapeutic agents.

An amino acid is any carboxylic acid having at least one free aminegroup and includes naturally occurring and synthetic amino acids.

Poly amino acids are either peptides or two or more amino acids linkedby a bond formed by other groups which can be linked, e.g. an ester,anhydride, or an anhydride linkage.

Peptides are two or more amino acids joined by a peptide bond. Peptidescan vary in length from dipeptides with two amino acids to poly peptideswith several hundred amino acids. See Chambers Biological Dictionary,editor Peter M. B. Walker, Cambridge, England: Chambers Cambridge, 1989,page 215. Special mention is made of di-peptides, tri-peptides,tetra-peptides, and penta-peptides.

Salts such as, for example, sodium salt of these carrier compounds canbe used as well.

Many of the compounds described herein are derived from amino acids.

Many of the compounds of the present invention can be readily preparedfrom amino acids including, but not limited to, aminocaprylic acid,butyrylhydroxaminic acid, aminophenylbutyric acid, aminophenylhexanoicacid, aminophenylpropionic acid, amino salicylic acid,aminophenylsuccinic acid, aminononanic acid, aminonicotinic acid, aminovalenic acid, aminophenylacetic acid, aminocaproic acid, aminoundecanoicacid, aminoheptanoic acid, aminohydroxybenzoic acid, and aminodecanoicacid by methods within the skill of those in the art based upon thepresent disclosure and the methods described in U.S. patent applicationSer. Nos. 60/017,902, filed Mar. 29, 1996; 08/414,654, filed Mar. 31,1995; 08/335,148, filed Oct. 25, 1994; and 60/003,111, filed Sep. 1,1995.

For example, these compounds may be prepared by reacting the single acidwith the appropriate agent which reacts with free amino moiety presentin the amino acids to form amides. Protecting groups may be used toavoid unwanted side reactions as would be known to those skilled in theart.

The carrier compound may be purified by recrystallization or byfractionation on solid column supports. Suitable recrystallizationsolvent systems include acetonitrile, methanol and tetrahydrofuran.Fractionation may be performed on a suitable solid column supports suchas alumina, using methanol/n-propanol mixtures as the mobile phase;reverse phase column supports using trifluoroacetic acid/acetonitrilemixtures as the mobile phase; and ion exchange chromatography usingwater as the mobile phase. When anion exchange chromatography isperformed, preferably a subsequent 0-500 mM sodium chloride gradient isemployed.

Delivery Systems

The compositions of the present invention may include one or more activeagents.

In one embodiment, compounds or salts of compounds 1-193 or poly aminoacids or peptides that include at least one of these compounds or saltsmay be used directly as a delivery carrier by simply mixing one or morecompound or salt, poly amino acid or peptide with the active agent priorto administration.

The administration mixtures are prepared by mixing an aqueous solutionof the carrier with an aqueous solution of the active ingredient, justprior to administration. Alternatively, the carrier and the biologicallyor chemically active ingredient can be admixed during the manufacturingprocess. The solutions may optionally contain additives such asphosphate buffer salts, citric acid, acetic acid, gelatin, and gumacacia.

Stabilizing additives may be incorporated into the carrier solution.With some drugs, the presence of such additives promotes the stabilityand dispersibility of the agent in solution.

The stabilizing additives may be employed at a concentration rangingbetween about 0.1 and 5% (W/V), preferably about 0.5% (W/V). Suitable,but non-limiting, examples of stabilizing additives include gum acacia,gelatin, methyl cellulose, polyethylene glycol, carboxylic acids andsalts thereof, and polylysine. The preferred stabilizing additives aregum acacia, gelatin and methyl cellulose.

The amount of active agent is an amount effective to accomplish thepurpose of the particular active agent. The amount in the compositiontypically is a pharmacologically, biologically, therapeutically, orchemically effective amount. However, the amount can be less than apharmacologically, biologically, therapeutically, or chemicallyeffective amount when the composition is used in a dosage unit form,such as a capsule, a tablet or a liquid, because the dosage unit formmay contain a multiplicity of carrier/biologically or chemically activeagent compositions or may contain a divided pharmacologically,biologically, therapeutically, or chemically effective amount. The totaleffective amounts can then be administered in cumulative unitscontaining, in total, pharmacologically, biologically, therapeuticallyor chemically active amounts of biologically or pharmacologically activeagent.

The total amount of active agent, and particularly biologically orchemically active agent, to be used can be determined by those skilledin the art. However, it has surprisingly been found that with somebiologically or chemically active agents, the use of the presentlydisclosed carriers provides extremely efficient delivery, particularlyin oral, intranasal, sublingual, intraduodenal, or subcutaneous systems.Therefore, lower amounts of biologically or chemically active agent thanthose used in prior dosage unit forms or delivery systems can beadministered to the subject, while still achieving the same blood levelsand therapeutic effects.

The amount of carrier in the present composition is a delivery effectiveamount and can be determined for any particular carrier or biologicallyor chemically active agent by methods known to those skilled in the art.

Dosage unit forms can also include any of excipients; diluents;disintegrants; lubricants; plasticizers; colorants; and dosing vehicles,including, but not limited to water, 1,2-propane diol, ethanol, oliveoil, or any combination thereof.

Administration of the present compositions or dosage unit formspreferably is oral or by intraduodenal injection.

The delivery compositions of the present invention may also include oneor more enzyme inhibitors. Such enzyme inhibitors include, but are notlimited to, compounds such as actinonin or epiactinonin and derivativesthereof. These compounds have the formulas below: ##STR194##

Derivatives of these compounds are disclosed in U.S. Pat. No. 5,206,384.Actinonin derivatives have the formula: ##STR195## wherein R⁵ issulfoxymethyl or carboxyl or a substituted carboxy group selected fromcarboxamide, hydroxyaminocarbonyl and alkoxycarbonyl groups; and R⁶ ishydroxyl, alkoxy, hydroxyamino or sulfoxyamino group. Other enzymeinhibitors include, but are not limited to, aprotinin (Trasylol) andBowman-Birk inhibitor.

The compounds and compositions of the subject invention are useful foradministering biologically or chemically active agents to any animalssuch as birds; mammals, such as primates and particularly humans; andinsects. The system is particularly advantageous for deliveringchemically or biologically or chemically active agents which wouldotherwise be destroyed or rendered less effective by conditionsencountered before the active agent its target zone (i.e. the area inwhich the active agent of the delivery composition are to be released)and within the body of the animal to which they are administered.Particularly, the compounds and compositions of the present inventionare useful in orally administering active agents, especially those whichare not ordinarily orally deliverable.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following examples illustrate the invention without limitation. Allparts are given by weight unless otherwise indicated.

EXAMPLE 1 Carrier Preparation

General Preparations of Carriers. The following procedures were used toprepare the compounds described herein. Many of the compounds wereprepared by reaction of the appropriate amino acid with the appropriateacid chloride. The preparation of compound 79 is given as arepresentative example of the compounds prepared in this manner.

Preparation of Compound 79. Method A. A 1 L round bottom flask fittedwith a magnetic stirrer was charged with 3-(4-aminophenyl)propionic acid(46.3 g, 0.28 moles, 1.17 equiv.) and 2 M aqueous sodium hydroxide (300mL). 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv.) wasadded portionwise over 1 h to the stirred solution. After the addition,the reaction was stirred for 2.5 h at ambient temperature, and the pH ofthe solution was kept at ca 10 by the addition of 10 M sodium hydroxide.The solution was then acidified with 1 M hydrochloric acid (3×100 mL),water (100 mL), and air dried. It was redissolved in boiling acetone (ca500 mL), decolorized with activated charcoal (3 g), and filtered. Water(1.5 L) was added to the filtrate to induce the formation of a brownoil. The brown oil solidified upon stirring at room temperature for 10min. The crude solid was collected by filtration and recrystallized from70% methanol-water (v/v) to afford compound 79 as a tan solid (39.5) g,50%).

Compounds 1, 5, 30, 31, 33, 36, 53-66, 68, 69, 71-74, 78, 80-88, 95,97-99, 102, 108-110, 112-115, 119, 121-126, 136, 137, 139, 141, 144,146, 147, 151, 152, 155-158, 160, 161, 163, 165, 166, 170, 172-174, 176,177, 184-186, 188, 189, 191 and 192 were also prepared by this process.

Preparation of Compound 79. Method B. A 2 L three-neck round bottomflask was fitted with a magnetic stirrer and two addition funnels underan argon atmosphere. A suspension of 3-(4-aminophenyl)propionic acid(46.3 g, 0.28 moles, 1.17 equiv.) in ethyl acetate (700 mL) was added tothe flask. A solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24moles, 1.00 equiv.) in ethyl acetate (250 mL) was charged to one of theaddition funnels and added dropwise over 1 h. Triethylamine (28.20 g,0.28 moles, 1.00 equiv.) was subsequently charged to the second funneland added dropwise over 15 min. The reaction was stirred at ambienttemperature for 3 h, and the solvent was evaporated in vacuo giving aresidual brown oil. Water (600 mL) was added to the residue followed bysodium hydroxide (2 M, 500 mL), and the mixture was stirred at ambienttemperature for 3 hours. The resultant brown solution was acidified with2 M hydrochloric acid (ca 1 L). After cooling the mixture in an ice bathfor 1 h, a yellow solid formed and was collected by filtration. Thesolid was washed with water (3×1.5 L) and recrystallized from 50%ethanol-water (v/v) to give compound 79 as a tan solid (59.2 g, 68%).

Compounds 18, 32, 37, 41, 168, 175, and 183 were also prepared by thisprocess.

Preparation of Compound 79. Method C. A 2 L round bottom flask equippedwith a magnetic stirrer and a reflux condenser was charged with asuspension of 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17equiv.) in dichloromethane (560 mL). Chlorotrimethylsilane (62.36 g,0.57 moles, 2.05 equiv.) was added in one portion, and the mixture washeated to reflux for 1 h under argon. The reaction was allowed to coolto room temperature and was placed in an ice bath (internal temperature<10° C.). The reflux condenser was replaced with an addition funnelcontaining triethylamine (42.50 g, 0.42 moles, 1.50 equiv.). Thetriethylamine was added dropwise over 15 min, and a yellow solid formedduring the addition. The funnel was replaced by another addition funnelcontaining a solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24moles, 1.00 equiv. in dichloromethane (100 mL). The solution was addeddropwise over 30 min. The reaction was stirred in the ice bath foranother 30 min and at ambient temperature for 1 h. The dichloromethanewas evaporated in vacuo to give a brown oil. The brown oil was cooled inan ice bath, and an ice-cold solution of 2 M sodium hydroxide (700 mL)was added. The ice bath was removed, and the reaction was stirred for 2h to afford a clear brown solution. The solution was acidified with 2 Msulfuric acid (400 mL) and stored at ca 5° C. for 1 hour. A yellow solidformed and was collected by filtration. The solid was washed with water(3×100 mL) and recrystallized from 50% ethanol-water (v/v) to affordcompound 79 as tan needles (64.7 g, 82%).

Compounds 2-4, 6-17, 19-29, 34, 38-40, 42-48, 50-52, 67, 70, 75-77,89-94, 96, 100, 101, 107, 111, 116-118, 127-132, 134, 135, 193, 142,143, 148, 149, 159, 162, 164, 169, 178-182, 187, and 190 were alsoprepared by this process.

Preparation of Compound 35. A solution of O-acetylsalicyloyl chloride(24.68 g, 124 mmol, 1 equiv) in tetrahydrofuran (300 mL) was cooled inan ice bath. Triethylamine (25 g, 249 mmol, 2 equiv) was added dropwisevia an additional funnel. The methyl 9-aminononanoate hydrochloride wasdissolved in DMF (190 mL, slightly warm to dissolve), charged to anaddition funnel and added dropwise to the above mixture. The reactionwas stirred in the ice-bath for 20 min and at room temperature for 2 h.Evaporation of the THF under reduced pressure gave a pink DMF solution.The pink solution was cooled in an ice-bath, and 2 M aqueous sodiumhydroxide (300 mL) was added. After being stirred at room temperaturefor 12 h, the mixture was acidified with 2 M hydrochloric acid (500 mL).The solution was cooled in an ice-bath, and a solid formed. The solidwas collected by filtration and was recrystallized from 50%ethanol/water to give compound 35 (32 g, 87%) as an off-white solid.

Preparation of Compound 49. 1-(2-hydroxyphenyl)-3-(4-methylbenzoate)-1,3-propane dione (3.00 g, 0.0101 mil.) is placed in a 100 mlround bottomed flask fitted with argon purge, magnetic stir bar and coldwater condenser. Glacial acetic acid (20 mls) and concentrated sulfuricacid (5 mls) were added, and heating of the reaction mixture wasinitiated. The reaction mixture was allowed to heat at reflux for 6 hbefore heating was discontinued. The reaction mixture was allowed tocome to room temperature, and then was poured into 100 mls of ice/water.This was stirred for approximately 1/2 h before the mixture wasfiltered, and a brown solid was isolated. The brown solid wasrecrystallized twice from acetic acid, yielding compound 49 as a tansolid (1.44 g, 53.8%).

Preparation of Compound 167. 2-coumaranone (4.21 g, 0.0314 mol) wasdissolved, with stirring, in acetonitrile (75 mls) in a 250 ml roundbottomed flask fitted with a magnetic stir bar, argon purge and coldwater condenser. Triethylamine (3.18 g, 0.0314 mol) and 8-aminocaprylicacid (5.00 g, 0.0314 mol) were added, and a tan slurry was formed.Heating was started, and the reaction mixture was allowed to refluxovernight. After heating overnight, thin layer chromatography of thereaction mixture (50% ethyl acetate/50% hexane) indicated that thereaction had gone to completion. Heating was stopped, the reactionmixture was allowed to cool to room temperature, and was concentrated invacuo. The resulting residue was taken up in methylene chloride, and waswashed with two, 100 ml portions of 1 N hydrochloric acid solution. Themethylene chloride layer was dried with sodium sulfate and wasconcentrated in vacuo. The resulting tan solid was allowed to dry invacuo overnight, yielding compound 167 as a tan solid (8.35 g, 70.4%).

Preparation of Compound 171. 1,4-benzodioxan-2-one (3.93 g, 0.0262 mol)was dissolved, with stirring, in acetonitrile (70 mls) in a 250 ml roundbottomed flask fitted with a magnetic stir bar, argon purge and coldwater condenser. Triethylamine (2.64 g, 0.0262 mol) and 8-aminocaprylicacid (500 g, 0.0262 mol) were added and a tan slurry was formed. Heatingwas started, and the reaction mixture was allowed to reflux forapproximately 3 hours. At this time, thin layer chromatography of thereaction mixture (50% ethyl acetate/50% hexane) indicated that thereaction had gone to completion. Heating was discontinued, and thereaction mixture was allowed to cool to room temperature and wasconcentrated in vacuo. The resulting residue was taken up in methylenechloride and was washed with a 100 ml portion of 1 N hydrochloric acidsolution. At this time, a tan solid was noted to precipitate, and it wasisolated by filtration. This tan solid was washed further with anadditional 100 ml portion of 1 N hydrochloric acid solution, and thenwith 100 ml of water. The resulting tan solid was allowed to dry invacuo overnight yielding Compound 171 as a tan solid (7.73 g, 95.6%).

Preparation of Compound 120. A solution of 3.00 g (18.3 mmol) of2-nitrophenylisocyanate and 5 mL of tetrahydrofuran was dropwise over 10min to an ice bath-cooled solution of 2.08 g (13.1 mmol) of8-aminocaprylic acid, 1.40 mL of 10 N NaOH and 40 mL of water. Thereaction mixture was stirred an additional 30 min, warmed to 25° C. andtreated with 3% HCl solution until the pH was 5. The yellow precipitatewas filtered off and rinsed with 100 ml of water. The yellow solid wasrecrystallized in 2-propanol and water to give 3.7 g of compound 120 aspale yellow crystals.

Compounds 104-106 were also prepared by this procedure.

Preparation of Compound 133. A suspension of 2.40 g (16.3 mmol) and 2.80g (15.6 mmol) of 4-(4aminophenyl)butyric acid in 20 mL of propyleneglycol, 2.40 mL (1.74 g, 17.3 mmol) of triethylamine and 10 mg (0.08mmol) of dimethylaminopyridine was heated to 140° C. The mixture becamea clear solution after 5 min at 140° C. After stirring for 330 min, thereaction mixture was cooled to 25° C. and diluted with 20 mL of water.The solid phthalimide which had formed was filtered off. The filtratewas acidified with 3% HCl solution. The resulting solid was filtered offand was recrystallized from 2-propanol and water to give 0.62 g ofcompound 133 as a tan solid.

Preparation of Compound 138. A solution of 1.73 g (12.9 mmol) ofphthalic dialdehyde, 2.04 g 8-aminocaprylic acid and 20 mL of aceticacid was heated to reflux for 10 min. The reaction mixture was cooled to40° C., diluted with water and extracted with CH₂ Cl₂ (2×20 mL). Theorganic phase was washed with water and brine, dried over Na₂ SO₄ andevaporated. The residue was dissolved in ether and extracted with 2NNaOH. The layers were separated. The aqueous layer was made acidic with3% HCl and extracted with CH₂ Cl₂. The organic phase was dried over Na₂SO₄ and evaporated. The yellow residue was crystallized fromacetonitrile and water to give 1.25 g of compound 138 as a yellow solid.

Preparation of Compound 140. A mixture of 1.40 g (9.48 mmol) of phthalicanhydride and 1.51 g (9.48 mmol) of 8-aminocaprylic acid was heated to150° C. for 5 min. Upon cooling, 2.61 g of solid compound 140 wasreceived.

Compound 150 was also prepared by this procedure.

Preparation of Compound 145. A suspension of 2.11 g (10.1 mmol) ethylcarbamoylanthranilic acid and 5 mL of CH₂ Cl₂ was treated with 2.20 mLof oxalyl chloride. After stirring for 1 h the volatiles were strippedoff. At that same time, a suspension of 1.60 g (10.1 mmol) of8-aminocaprylic acid and 15 mL of CH₂ Cl₂ was treated with 2.60 mL (2.23g, 20.5 mmol) of TMSCl. This mixture was heated to reflux for 90 min,cooled in an ice bath and treated with 4.30 mL (3.12 g, 30.9 mmol) oftriethylamine. Five min later, a slurry of the residue from the oxalylchloride reaction in 20 mL of CH₂ Cl₂ was added. The reaction mixturewas warmed to 25° C. and stirred overnight. Upon acidification of themixture with 3% HCl, a white solid formed. The solid was filtered offand recrystallized from EtOH and water to give 1.88 g of compound 145.

Compound 153 was also prepared by this procedure.

Preparation of Compound 154. A suspension of 4.02 g (25.6 mmol) oftrans-4-aminomethylcyclohexane-carboxylic acid, 4.18 g (25.6 mmol) ofisatoic anhydride, 20 mL of CH₂ Cl₂, 20 mL of dioxane, and 4 mL of waterwas heated to reflux for 12 h. The solution was cooled to 25° C. andextracted with ether (4×20 mL). The organic layer was dried over Na₂ SO₄and concentrated. The resulting solid was recrystallized from EtOH andwater to give 4.95 g of compound 154.

Compound 103 is available from Aldrich Chemical Company, Inc.,Milwaukee, Wis.

EXAMPLE 2 Parathyroid Hormone Dosing Solutions

Intracolonic ("IC") dosing compositions containing 100 mg/kg of carrierand 25 μg/kg of parathyroid hormone in 25% aqueous propylene glycol ororal gavage "PO") dosing solution containing 400 mg/kg of carrier and100 μg/kg of parathyroid hormone in water, were prepared with carriers9, 33, 35, 77, 79, 109, 110, 123, 136, 141, and 169. The dosingsolutions are designated P-carrier number-DS.

Comparative Example 2A Parathyroid Hormone Dosing Solutions

An intracolonic dosing composition containing 100 mg/kg of a carrierhaving the formula ##STR196## and 25 ug/kg of parathyroid hormone in 25%aqueous propylene glycol was prepared. The dosing solution is identifiedas P-9A-DS.

EXAMPLES 3 In vivo Parathyroid Hormone Delivery

Male Sprague-Dawley rats weighing between 200-250 g were fasted for 24hours and were administered ketamine (44 mg/kg) and chlorpromazine (1.5mg/kg) 15 minutes prior to dosing. The rats were administered one ofdosing solutions P-9-DS, P-33-DS, P-35-DS, P-77-DS, P-79-DS, andP-141-DS by oral gavage ("PO") or intra-colonic instillation ("IC").Blood samples were collected serially from the tail artery for serumdetermination of parathyroid hormone concentration. Serum parathyroidhormone concentrations were quantified by a parathyroid hormoneimmunoaccuracy test host.

Results are illustrated in Table 2, below.

Comparative Example 3A In vivo Parathyroid Hormone Delivery

The procedure of Example 3 was followed substituting dosing solutionP-9A-DS for dosing solution P-9-DS. Results are illustrated in Table 2,below.

Comparative Example 3B In vivo Parathyroid Hormone Delivery

The procedure of Example 3 was followed with a dosing solution (at adose of 25 μg/kg of parathyroid hormone (intra-colonic) or 100 μg/kg ofparathyroid hormone (oral)), P-.O slashed.A-DS, that omitted thecarrier.

Results are illustrated in Table 2, below.

                  TABLE 2                                                         ______________________________________                                        In vivo Parathyroid Hormone Delivery                                                           Mean Peak Serum [PTH] ±                                   Dosing Solution  Standard Deviation (pg/ml)                                   ______________________________________                                        P-9-DS           155 ± 105 (IC)                                            P-33-DS          58 ± 18 (IC)                                              P-35-DS          50 ± 27 (IC)                                              P-77-DS          358 ± 274 (PO)                                            P-79-DS          521 ± 128 (PO)                                            P-109-DS         128 ± 25 (IC)                                             P-110-DS         35 ± 11 (IC)                                              P-123-DS         49 ± 22 (IC)                                              P-136-DS         106 ± 72 (IC)                                             P-141-DS         120 ± 120 (PO)                                            P-169-DS         19 ± 33 (IC)                                              P-9A-DS          116 ± 48 (IC)                                             P-φA-DS      11 ± 2 (PO), 27 ± 27 (IC)                              ______________________________________                                    

EXAMPLES 4 Recombinant Human Growth Hormone Dosing Solutions

Intracolonic dosing compositions containing 25 mg/kg of carrier and 1mg/kg of rHGH in phosphate buffer or oral gavage dosing solutionscontaining 600 mg/kg of carrier and 3 mg/kg of rHGH in phosphate bufferwere prepared with carriers 9, 35, 36, 47, 62, 64, 67, 77, 79, 90, 94,107, 109, 136, and 141.

The dosing solutions are designated R- carrier number-DS.

Comparative Example 4A Recombinant Human Growth Hormone Dosing Solutions

An intracolonic dosing solution was prepared according to the procedureof Example 4, substituting a carrier having the formula ##STR197## forthe carrier. This dosing solution is designated as R-35A-DS.

Comparative Example 4B Recombinant Human Growth Hormone Dosing Solutions

An intracolonic dosing solution was prepared according to the procedureof Example 4, substituting a carrier having the formula ##STR198## forthe carrier. This dosing solution is designated as R-35B-DS.

Comparative Example 4C Recombinant Human Growth Hormone Dosing Solutions

An intracolonic dosing solution was prepared according to the procedureof Example 4, substituting a carrier having the formula ##STR199## forthe carrier. This dosing solution is designated as R-9A-DS.

EXAMPLE 5 In Vivo Recombinant Human Growth Hormone Delivery

Male Sprague-Dawley rats weighing 200-250 g were fasted for 24 hours andadministered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15minutes prior to dosing. The rats were administered one of the dosingsolutions of Example 3 by either oral gavage or intracolonicinstillation. Blood samples were collected serially from the tail arteryfor determination of serum rHGH concentrations. Serum rHGHconcentrations were quantified by an rHGH immunoassay test kit.

Results are illustrated in Table 3, below.

Comparative Example 5A In Vivo Recombinant Human Growth Hormone Delivery

The procedure of Example 5 was followed, substituting the dosingsolutions of Comparative Examples 3A-3C for the dosing solutions.Results are illustrated in Table 3, below.

Comparative Example 5B In Vivo Recombinant Human Growth Hormone Delivery

The procedure of Example 5 was followed, with dosing solutions of activeagent (at a dose of 1 mg of rHGH/kg (intracolonic) or 3 mg of rHGH/kg(oral) and no carrier. These dosing solutions are designated R-.Oslashed.D-DS and R-.O slashed.E-DS, respectively. Results areillustrated in Table 3, below.

                  TABLE 3                                                         ______________________________________                                        Vivo Recombinant Human Growth Hormone Delivery                                                 Mean Peak Serum [rHGH] ±                                  Dosing Solution  Standard Deviation (ng/ml)                                   ______________________________________                                        R-9-DS           125 ± 34 (IC)                                             R-35-DS          41 ± 46 (PO)                                                               108 ± 56 (IC)                                             R-36-DS          28 ± 11 (IC)                                              R-47-DS          0 (IC)                                                       R-62-DS          11 ± 12 (IC)                                              R-64-DS          72 ± 22 (PO)                                              R-67-DS          19 ± 22 (PO)                                                               88 ± 24 (IC)                                              R-77-DS          34 ± 10 (PO)                                              R-79-DS          62 ± 51 (PO)                                              R-90-DS          9 ± 13 (PO)                                               R-94-DS          39 ± 35 (PO)                                              R-107-DS         0 ± 0 (PO)                                                R-109-DS         128 ± 25 (IC)                                             R-136-DS         106 ± 72 (IC)                                             R-141-DS         95 ± 14 (IC)                                              R-35A-DS         17 ± 3 (IC)                                               R-35B-DS         42 ± 28 (IC)                                              R-9A-DS          55 ± 17 (IC)                                              R-φD-DS      0 ± 0 (IC)                                                R-φE-DS      0 ± 0 (IC)                                                ______________________________________                                    

EXAMPLE 6 In Vivo Interferon Delivery

An intracolonic dosing composition containing 50 mg/kg of carrier 9 and250 μg/kg of interferon in 50% propylene glycol was prepared. Rats wereadministered the dosing composition by intracolonic instillation.Delivery was evaluated by use of an ELISA assay for human interferon afrom Biosource, Inc. Mean peak serum interferon concentration was2611±695.

Comparative Example 6A In Vivo Interferon Delivery

Rats were administered, orally and by intracolonic instillation, dosingsolutions of 1 mg/kg of interferon and no carrier. Delivery wasevaluated according to the procedure of Example 6. Mean peak seruminterferon concentration was 1951±1857 (PO) and 79±100 (IC).

EXAMPLE 7 Heparin Dosing Solutions

Intracolonic dosing compositions containing 50 mg/kg of carrier and 25mg/kg of heparin in 25% aqueous propylene glycol or oral gavage dosingsolutions containing 300 mg/kg of carrier and 100 mg/kg of heparin in25% aqueous propylene glycol were prepared with carriers 9, 35, 47, 50,58, 62, 64, 67, 76, 96, 102, 109, 110, 111, 117, 122, 123, 139, 141,144, and 169. The dosing solutions are designated H-carrier number-DS.

Comparative Example 7A Heparin Dosing Solutions

Comparative intracolonic dosing compositions were prepared according tothe procedure of Example 7, substituting the following carriers for thecarrier. ##STR200##

These dosing solutions are designated H-35A-DS, H-35B-DS, and H-109A-DS,respectively.

EXAMPLES 8 In Vivo Evaluation of Heparin in Rats

The dosing solutions of Example 7 were administered to fasted ratseither by oral gavage or intracolonic instillation.

Blood samples were collected by cardiac puncture following theadministration of ketamine (44 mg/kg). Heparin activity was determinedby utilizing the activated partial thromboplastin time (APTT) accordingto the method of Henry, J. B., Clinical Diagnosis and Management byLaboratory Methods; Philadelphia, Pa.; W. B. Saunders (1979).

Results are in illustrated in Table 4, below.

Comparative Examples 8A In Vivo Evaluation of Heparin in Rats

The dosing solutions of Comparative Example 7A were administered tofasted rats by intracolonic instillation. Blood samples were collectedand heparin activity was determined by the method of Example 8.

Results are illustrated in Table 4, below.

Comparative Example 8B In Vivo Evaluation of Heparin in Rats

An intracolonic dosing solution of 25 mg/kg of heparin and an oralgavage dosing solution of 100 mg/kg of heparin were administered tofasted rats. These dosage solutions were designated H-.O slashed.A-DSand H-.O slashed.B-DS, respectively.

Blood samples were collected, and heparin activity was determined by themethods of Example 8.

Results are illustrated in Table 4, below.

                  TABLE 4                                                         ______________________________________                                        In Vivo Evaluation of Heparin in Rats                                         Dosing Solution  Heparin APTT (sec)                                           ______________________________________                                        H-9-DS           48 ± 18 (IC)                                              H-35-DS          54 ± 27 (PO), 177 ± 85 (IC)                            H-47-DS          30 ± 14 (IC)                                              H-50-DS          40 ± 22 (IC)                                              H-58-DS          24 ± 4 (IC)                                               H-62-DS          37 ± 13 (IC)                                              H-64-DS          59 ± 28 (PO), 168 ± 75 (IC)                            H-67-DS          76 ± 36(IC)                                               H-76-DS          63 ± 27 (PO)                                              H-96-DS          36 ± 8 (IC)                                               H-102-DS         111 ± 108 (IC)                                            H-109-DS         56 ± 28 (IC)                                              H-110-DS         37 ± 9 (IC)                                               H-111-DS         71 ± 39 (IC)                                              H-117-DS         140 ± 128 (IC)                                            H-122-DS         49 ± 21 (IC), 207 ± 7 (PO)                             H-123-DS         42 ± 14 (PO)                                              H-139-DS         31 ± 11 (IC)                                              H-141-DS         59 ± 26 (IC)                                              H-144-DS         26 ± 3 (IC)                                               H-35A-DS         61 ± 29 (IC)                                              H-35B-DS         51 ± 30 (IC)                                              H-169-DS         23 ± 2 (IC)                                               H-φA-DS      123 ± 2 (PO)                                              H-φB-DS      33 ± 6 (IC)                                               ______________________________________                                    

The above mentioned patents, applications, test methods, andpublications are hereby incorporated by reference in their entirety.

Many variations of the present invention will suggest themselves tothose skilled in the art in light of the above detailed description. Allsuch obvious variations are within the full intended scope of theappended claims.

What is claimed is:
 1. A composition comprising:(A) at least one activeagent; and (B) a compound having the following formula ##STR201## or asalt thereof.
 2. A composition as defined in claim 1, wherein saidactive agent is selected from the group consisting of a biologicallyactive agent, a chemically active agent, or a combination thereof.
 3. Acomposition as defined in claim 2, wherein said biologically activeagent comprises at least one peptide, mucopolysaccharide, carbohydrate,or lipid.
 4. A composition as defined in claim 2, wherein saidbiologically active agent is selected from the group consisting of humangrowth hormone, bovine growth hormone, growth hormone-releasing hormone,an interferon, interleukin-II, insulin, heparin, low molecular weightheparin, calcitonin, erythropoietin, atrial naturetic factor, anantigen, a monoclonal antibody, samatostatin, adrenocorticotropin,gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium,vancomycin, parathyroid hormone, desferrioxamine (DFO), or anycombination thereof.
 5. A composition as defined in claim 4, whereinsaid biologically active agent comprises an interferon, interleukin-II,insulin, heparin, low molecular weight heparin, calcitonin, oxytosin,vasopressin, vancomycin, DFO, parathyroid hormone, and combinationsthereof.
 6. A composition as defined in claim 2, wherein saidbiologically active agent comprises recombinant human growth hormone. 7.A composition as defined in claim 2, wherein said biologically activeagent comprises heparin.
 8. A composition as defined in claim 2, whereinsaid biologically active agent agent comprises low molecular weightheparin.
 9. A composition as defined in claim 1, wherein said carriercomprises a poly(amino acid).
 10. A composition as defined in claim 1,wherein said carrier comprises a polypeptide.
 11. A dosage unit formcomprising:(A) a composition as defined in claim 1; and (B) (a) anexcipient (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) aplasticizer, (f) a colorant, (g) a dosing vehicle, or (h) anycombination thereof.
 12. A composition as defined in claim 11, whereinsaid active agent is selected from the group consisting of abiologically active agent, a chemically active agent, or a combinationthereof.
 13. A composition as defined in claim 12, wherein saidbiologically active agent comprises at least one peptide,mucopolysaccharide, carbohydrate, or lipid.
 14. A composition as definedin claim 12, wherein said biologically active agent is selected from thegroup consisting of human growth hormone, bovine growth hormone, growthhormone-releasing hormone, an interferon, interleukin-II, insulin,heparin, low molecular weight heparin, calcitonin, erythropoietin,atrial naturetic factor, an antigen, a monoclonal antibody,samatostatin, adrenocorticotropin, gonadotropin releasing hormone,oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone,desferrioxamine (DFO), or any combination thereof.
 15. A composition asdefined in claim 14, wherein said biologically active agent comprises aninterferon, interleukin-II, insulin, heparin, low molecular weightheparin, calcitonin, oxytosin, vasopressin, vancomycin, DFO, parathyroidhormone, and combinations thereof.
 16. A composition as defined in claim11, wherein said biologically active agent comprises recombinant humangrowth hormone.
 17. A composition as defined in claim 11, wherein saidbiologically active agent comprises heparin.
 18. A composition asdefined in claim 11, wherein said biologically active agent agentcomprises low molecular weight heparin.
 19. A dosage unit form asdefined in claim 11, comprising a tablet, a capsule, or a liquid.
 20. Adosage unit form as defined in claim 15, wherein said dosing vehicle isselected from the group consisting of water, 1,2-propane diol, ethanol,or any combination thereof.
 21. A method for administering abiologically-active agent to an animal in need of said agent, saidmethod comprising administering orally to said animal a composition asdefined in claim
 2. 22. A compound having the formula ##STR202## or asalt thereof.
 23. A method for preparing a composition, said methodcomprising mixing:(A) at least one active agent; (B) at least onecarrier compound as defined in claim 22; and (C) optionally, a dosingvehicle.